Summary In general, rates of breast cancer are lower in low-income and middle-income countries (LMCs) than they are in more industrialised countries of North America and Europe. This lower incidence ...means that screening programmes aimed at early detection in asymptomatic women would have a lower yield—ie, substantially more women would need to be examined to find a true case of breast cancer. Because the average age of breast cancer is generally younger in LMCs, it has been suggested that breast-cancer screening programmes begin at an earlier age in these settings. However, the younger average age of breast cancer is mainly driven by the age distribution of the population, and fewer older women with breast cancer, rather than by higher age-specific incidence rates in younger women. Resources in LMCs might be better used to raise awareness and encourage more women with palpable breast lumps to seek and receive treatment in a timely manner.
As the world exits the global pandemic caused by the previously unknown SARS-CoV-2, we also mark the 30th anniversary of p53 being named "molecule of the year" by
based on its role as a tumor ...suppressor. Although p53 was originally discovered in association with a viral protein, studies on its role in preventing carcinogenesis have far overshadowed research related to p53's role in viral infections. Nonetheless, there is an extensive body of scientific literature demonstrating that p53 is a critical component of host immune responses to viral infections. It is striking that diverse viruses have independently developed an impressive repertoire of varied mechanisms to counter the host defenses that are mediated by and through p53. The variety of ways developed by viruses to disrupt p53 in their hosts attests to the protein's importance in combatting viral pathogens. The present perspective aims to make the case that p53 ought to be considered a virus suppressor in addition to a tumor suppressor. It is hoped that additional research aimed at more fully understanding the role of p53 in antiviral immunity will result in the world being better positioned for the next pandemic than it was when SARS-CoV-2 emerged to produce COVID-19.
Summary Cancer control in Africa is complicated due to large differences in cancer incidence between countries caused by differences in exposure to known risk factors. For example, substantial ...differences are seen when selected cancers in north Africa are compared with those in sub-Saharan Africa. In the future, population growth and demographic shifts are likely to have profound effects on the prevalence of cancer across the continent. Likewise, many factors outside of health care such as language differences, conflict, and poverty can affect cancer control efforts. Although cooperation in cancer control efforts is desirable, differences in cultural and geopolitical factors that characterise African countries and their populations, together with the sheer size of the continent, present unique challenges to effective cancer control. This Series paper discusses factors related to the size, diversity, and conditions within Africa that present barriers to optimal collaboration in cancer control efforts across the continent.
Abstract
Intrinsic therapeutic resistance especially in cancer stem cells (CSCs) together with extensive tumor cell infiltration and restricted permeation of the blood-brain barrier (BBB) by drugs ...may all contribute to the treatment failure in patients with glioblastoma multiforme (GBM). Accumulating evidence suggests that long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a role in tumor cell infiltration and therapeutic resistance of GBM. Using our tumor-targeted nanocomplex, we have modulated the expression of MALAT1 and investigated its impact on GBM cells. Importantly, our nanocomplex is able to target CSCs that are considered to be the prime culprits in therapeutic resistance and recurrence of GBM. Attenuation of MALAT1 by RNA interference significantly lowered the growth, motility and stemness of GBM cells. In addition, silencing of MALAT1 clearly improved the sensitivity of GBM cells to chemotherapeutic agents including the current first-line therapy of GBM temozolomide (TMZ). In animal models of GBM, tumor involution with a modest but statistically significant survival benefit was achieved with concurrent treatment of TMZ and nanocomplex-mediated silencing of MALAT1. These results suggest that combining standard TMZ treatment with lncRNA-targeting therapies using our nanocomplex could substantially enhance the very poor prognosis for GBM patients.
Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood–brain barrier (BBB) play a major ...role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review.
•GBM is the most aggressive and lethal type of brain tumor with a poor prognosis.•CSCs are the primary cause of current chemoresistance and recurrence of GBM.•Novel strategies are needed to overcome current therapeutic resistances in GBM.•New CSC-targeted therapies are being developed with nanomedicine.•Nanomedicine offers possibilities to overcome CSC-mediated therapeutic resistances.
Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the ...chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach.PurposeAtypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach.We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT.MethodsWe tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT.Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice.ResultsRestoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice.Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.ConclusionCollectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.
Nanomedicine is an emerging and rapidly evolving field and includes the use of nanoparticles for diagnosis and therapy of a variety of diseases, as well as in regenerative medicine. In this ...mini-review, leaders in the field from around the globe provide a personal perspective on the development of nanomedicine. The focus lies on the translation from research to development and the innovation supply chain, as well as the current status of nanomedicine in industry. The role of academic professional societies and the importance of government funding are discussed. Nanomedicine to combat infectious diseases of poverty is highlighted along with other pertinent examples of recent breakthroughs in nanomedicine. Taken together, this review provides a unique and global perspective on the emerging field of nanomedicine.
Summary The purpose of the Breast Health Global Initiative (BHGI) 2010 summit was to provide a consensus analysis of breast cancer control issues and implementation strategies for low-income and ...middle-income countries (LMCs), where advanced stages at presentation and poor diagnostic and treatment capacities contribute to lower breast cancer survival rates than in high-income countries. Health system and patient-related barriers were identified that create common clinical scenarios in which women do not present for diagnosis until their cancer has progressed to locally advanced or metastatic stages. As countries progress to higher economic status, the rate of late presentation is expected to decrease, and diagnostic and treatment resources are expected to improve. Health-care systems in LMCs share many challenges including national or regional data collection, programme infrastructure and capacity (including appropriate equipment and drug acquisitions, and professional training and accreditation), the need for qualitative and quantitative research to support decision making, and strategies to improve patient access and compliance as well as public, health-care professional, and policy-maker awareness that breast cancer is a cost-effective, treatable disease. The biggest challenges identified for low-income countries were little community awareness that breast cancer is treatable, inadequate advanced pathology services for diagnosis and staging, and fragmented treatment options, especially for the administration of radiotherapy and the full range of systemic treatments. The biggest challenges identified for middle-resource countries were the establishment and maintenance of data registries, the coordination of multidisciplinary centres of excellence with broad outreach programmes to provide community access to cancer diagnosis and treatment, and the resource-appropriate prioritisation of breast cancer control programmes within the framework of existing, functional health-care systems.
Despite its anticipated clinical potential, anti‐PD‐1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti‐PD‐1 antibody with ...other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti‐PD‐1‐insensitive tumors. Here, we evaluated whether introducing wild‐type p53 gene via a tumor‐targeting nanomedicine (termed SGT‐53) could provide immune stimulation and augment anti‐PD‐1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti‐PD‐1 monotherapy had no demonstrable therapeutic effect. However, combining anti‐PD‐1 with our investigational nanomedicine SGT‐53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T‐cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT‐53 upregulated PD‐L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT‐53 can boost antitumor immunity and sensitize glioblastoma to anti‐PD‐1 therapy by converting immunologically “cold” tumors into “hot” tumors. Combining SGT‐53 with anti‐PD‐1 might benefit more patients from anti‐PD‐1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma.
What's new?
Antibodies targeting the programmed cell death protein 1 (anti‐PD‐1) pathway represent a promising immunotherapeutic strategy against glioblastoma. Nonetheless, in recent trials, significant numbers of glioblastoma patients failed to respond to anti‐PD‐1. Here, the authors explored the possibility of overcoming this insensitivity by combining anti‐PD‐1 with SGT‐53, a tumor‐targeting nanomedicine that restores p53 function. In glioblastoma mouse models, the combined immunotherapy approach effectively inhibited tumor growth and increased intratumoral infiltration of immune effector cells. Increased immunogenicity was associated with significant survival benefits. The data provide a strong mechanistic rationale for combining SGT‐53 nanomedicine and anti‐PD‐1 immunotherapy in the treatment of glioblastoma.
SGT-53 is a novel investigational agent that comprises an immunoliposome carrying a plasmid vector driving expression of the human
gene that encodes wild-type human p53. SGT-53 is currently in phase ...II human trials for advanced pancreatic cancer. Although p53 is best known as a tumor suppressor, its participation in both innate and adaptive immune responses is well documented. It is now clear that p53 is an important component of the host response to various viral infections. To facilitate their viral life cycles, viruses have developed a diverse repertoire of strategies for counteracting the antiviral activities of host immune system by manipulating p53-dependent pathways in host cells. Coronaviruses reduce endogenous p53 levels in the cells they infect by enhancing the degradation of p53 in proteasomes. Thus, interference with p53 function is an important component in viral pathogenesis. Transfection of cells by SGT-53 has been shown to transiently produce exogenous p53 that is active as a pleiotropic transcription factor. We herein summarize the rationale for repurposing SGT-53 as a therapy for infection by SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Because p53 regulation was found to play a crucial role in different infection stages of a wide variety of viruses, it is rational to believe that restoring p53 function based on SGT-53 treatment may lead to beneficial therapeutic outcomes for infectious disease at large including heretofore unknown viral pathogens that may emerge in the future.
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